Project Summary This application describes experiments that will shed light on the bacterial cell cycle and elucidate ways in which this process might be targeted by small molecules to cure infections resistant to current antibiotics. Central to the bacterial cell cycle is a protein called FtsZ, which is similar in structure to mammalian tubulin. Although many natural products and other small molecules target tubulin effectively, resulting in therapies for curing cancer, the ability to target the bacterial cell cycle and halt resistant infections has not been fully explored. We will develop efficient syntheses of several FtsZ-targeting natural products and we will use NMR spectroscopy to discern how these molecules interact with FtsZ. With this insight, we will then use computational chemistry to interpret the molecular interactions that result in binding and how to design more potent molecules. We will also use information provided by X-ray crystallography in the design of protein- mimicking small molecules that can disrupt bacterial cell division and possibly halt the bacterial response to DNA damage, which could render the organism more susceptible to current antibiotics. Finally, we will use chemical synthesis and new proteomic techniques to elucidate the target of a compound that halts bacterial cell division without acting on FtsZ. This compound may target one of the other fourteen proteins required for cell division, and this would be the first small molecule inhibitor of one of these proteins. The proposed research will reveal new potential targets within that bacterial cell cycle that may enable new medicines to be developed to combat resistant infections. Many diseases caused by bacteria, such as "staph" infections caused by MRSA (methicillin-resistant Staphylococcus aureus), can no longer be cured with current antibiotics because the bacteria have developed resistance. Our research will result in knowledge about how bacteria divide and multiply so that this essential process, which may not mutate and develop resistance as quickly as other processes, can be targeted with new drugs